Diabetic retinopathy is among the most common complications of diabetes. Basement membrane thickening and pericyte loss are early changes associated with the development of diabetic retinopathy. I speculate that these events disrupt Notch signaling, which depends upon juxtaposition of cellular membranes, and also impair cell signaling cross-talk between Notch and TGF-2 signaling. To test this hypothesis, I propose to: (i) establish a cell culture system to measure cell-cell interactions mediated by Notch using imaging methods; (ii) examine how Notch/TGF-2 signaling is affected in vascular cells cultured under conditions resembling a diabetic environment; and, (iii) use mouse models and postmortem human eye tissue for examining the role of Notch/TGF- 2 interactions in diabetic retinopathy. I propose a training plan that will enable me to accomplish the proposed experiments and a strategy for transition towards career independence. PUBLIC HEALTH RELEVANCE: In this research proposal I propose to test the hypothesis that a signaling pathway termed Notch plays a role in the development of diabetic retinopathy, which is a prevalent cause of vision loss. I propose a training plan that will allow me to study this problem using cell culture systems and in vivo models of diabetes.